HOMOCYSTEINE, A CANDIDATE PERIPHERAL BIOMARKER FOR CEREBRAL mGluR5 ACTIVITY IN COMORBID ALCOHOL- AND TOBACCO USE DISORDER

酒精和烟草使用障碍是严重的公共卫生问题，但只有少数 药物被批准用于治疗这两种疾病。迫切需要找出新的 药物开发的神经递质靶点。有明显的临床前和新兴临床 谷氨酸(Glu)系统在糖尿病的发生和维持中发挥核心作用的证据 经常使用酒精和尼古丁，戒除一段时间后恢复正常。临床前 研究已经证明了代谢性谷氨酸受体5型(MGluR5)的特殊作用。 这项研究将检测酒精使用障碍(AUD)患者的mGluR5受体 与年龄匹配的健康对照组(HC)和烟草使用障碍患者(TUD)；它还将澄清 吸烟和TUD对AUD人群的影响正电子发射断层扫描(PET)，使用 特定的mGluR5放射性配体[18F]FPEB，将定量mGluR5结合潜力(BPND)，这是一种PET衍生的 与受体可获得性和密度有关的指标。具体地说，目标1将比较mGluR5 BPND 未接受治疗的患者(N=80)与HC参与者(N=40)比较。此外，在澳元中 受试者，吸烟者(AUD+TUD；N=40)将与不吸烟者(仅AUD；N=40)进行比较(目标2)， 仅TUD参与者(N=40)将与AUD+TUD(N=40)和HC参与者(N=40)进行比较 (目标3)。所有参与者将完成标准化的评估程序，以确定酒精和 烟草使用史。符合条件的AUD参与者将被临床研究单位(CRU)接纳，并 完成三天的非药物酒精戒毒；吸烟者将保持一贯的 吸烟的数量/频率；戒酒和戒酒欲望的测量以及情绪意愿 将被获得。在第4天，AUD受试者完成mGluR5 BPND的PET测量。在第五天，澳元 受试者参加酒精刺激的累进比率程序，以量化反应的程度 用于饮酒和饮酒。除了小组之间的比较，我们还将检查 [18F]FPEB、BPND与CRU戒酒和渴求测量(AIM)的关系 4)、酒精刺激的应答量(目标5)，以及下列基线评估措施 使用酒精和烟草的数量和频率(目标6)。到目前为止，临床上的治疗益处 批准或研究的AUD药物一直不多。但是，有多行 证据表明，mGluR5位点在动物模型中高度敏感，并显示出作为一种 治疗的目标。这项提议将首次在患有AUD的活体人类中表征mGluR5， 为了阐明烟草使用在这一人群中的调节作用，并检查 MGluR5是酒精和烟草使用的关键行为指标。重要的是，mGluR5阴性 几家制药公司正在开发变构调节剂(NAMS)，并正在进行 几种精神疾病的临床试验。这项拟议的研究将为未来的研究奠定基础 直接检测mGluR5-NAMS对脑mGluR5占用和行为的治疗作用 AUD临床人群的结局。

Alcohol and tobacco use disorders are serious public health problems, but only a small number of medications are approved for treatment of either disorder. There is a pressing need to identify new neurotransmitter targets for medication development. There is clear preclinical and emerging clinical evidence that the glutamate (Glu) system plays a central role in development and maintenance of regular alcohol and nicotine use, withdrawal and reinstatement after a period of abstinence. Pre- clinical studies have demonstrated a specific role for the metabotropic glutamate receptor, type 5 (mGluR5). This study will examine the mGluR5 receptor in persons with alcohol use disorder (AUD) compared with age-matched healthy controls (HC) and persons with tobacco use disorder (TUD); it also will clarify the effects of smoking and TUD in the AUD population. Positron emission tomography (PET), using the specific mGluR5 radioligand [18F]FPEB, will quantify mGluR5 binding potential (BPND), a PET-derived measure that relates to receptor availability and density. Specifically, aim 1 will compare mGluR5 BPND in non-treatment seeking AUD (N=80) versus HC participants (N=40). Additionally, among AUD subjects, smokers (AUD+TUD; N=40) will be compared with nonsmokers (AUD only; N=40) (aim 2), and TUD only participants (N=40) will be compared with AUD+TUD (N=40) and HC participants (N=40) (aim 3). All participants will complete standardized assessment procedures to characterize alcohol and tobacco use history. Eligible AUD participants will be admitted to the Clinical Research Unit (CRU) and complete a three day, unmedicated alcohol detoxification; smokers will maintain their usual quantity/frequency of cigarette use; measures of alcohol withdrawal and craving as well as mood will be obtained. On day 4, AUD subjects complete PET measurement of mGluR5 BPND. On day 5, AUD subjects participate in an alcohol-motivated progressive ratio procedure to quantify extent of responding for and consumption of alcohol. In addition to the between-group comparisons, we will examine relationships between [18F]FPEB BPND and CRU measures of alcohol withdrawal and craving (aim 4), amount of alcohol-motivated responding (aim 5), as well as baseline assessment measures of amount and frequency of alcohol and tobacco use (aim 6). To date, therapeutic benefit of clinically approved or investigational AUD medications has been modest. However, there are multiple lines of evidence indicating that the mGluR5 site is highly sensitive in animal models, and shows promise as a target for treatment. This proposal will be the first to characterize mGluR5 in living humans with AUD, to clarify the modulating role of tobacco use in this population and to examine the relationship of mGluR5 to key behavioral measures of alcohol and tobacco use. Importantly, mGluR5 negative allosteric modulators (NAMs) are in development by several drug companies and are undergoing clinical trials for several psychiatric diseases. This proposed study will set the stage for future research to directly test the therapeutic effects of mGluR5 NAMs on brain mGluR5 occupancy and behavioral outcomes in AUD clinical population.